Our goal is to define the role(s) played by the fibroblast during fibrosis, cardiac remodeling and the development of heart failure in two mouse models of human disease. Fibrosis is increasingly recognized as an important contributor to progressive heart disease and failure but there is a striking deficit in our understanding of fibroblast-based signaling and its role in these processes. We hypothesize that TGFp signaling processes that are fibroblast-based play a critical role the fibrotic response in sarcomere- based and non-sarcomere-based disease. We will precisely ablate discrete signaling pathways in the fibroblast during cardiac disease development. Two models will be used. Model 1 is a sarcomere protein- based model in which an N-terminal fragment of cardiac myosin heavy chain C (cMyBP-C) can be inducibly expressed specifically in the cardiomyocyte. This fragment uniquely presents in the failing or diseased human heart. Expression of this polypeptide results in cardiac hypertrophy, fibrosis and transition to failure. Model 2 utilizes a mutant aB crystallin (CryAB'^^^??) that is causative for human skeletal and cardiac disease, but is a non-sarcomeric protein-based model of cardiac failure. This model is also characterized by hypertrophy, extensive fibrosis and heart failure.
Aim 1 will test the hypothesis that canonical TGF(3 signaling plays a critical role in fibrosis during hypertrophy and failure in the cMyBP-C truncation model. The necessity and sufficiency of different pathways active in the fibroblast will be defined by breeding the transgene into a novel inducible kniockout set of mice in which we are able to ablate either canonical or non-canonical TGF(3 signaling. The mutant cMyBP-C allele will be bred into a mouse line with activated fibroblast-specific expression of inducible Cre. Offspring containing both the transgene and inducible Cre will then be bred into lines with either a smad2/3-loxP or tgfprl-loxP allele.
Aim 2 will test and define the role of TGFp signaling in our CryAB^^^?? model in a similar set of experiments.
These aims will define the role of fibroblast-based signaling.
Aim 3 willdetermine, in both the CryAB and cMyBP-C models, the importance of non-TGFp cytokine signaling during cardiac disease. The experiments outlined in Aims 1 and 2 will be repeated, but on a genetic background in which we are able to modulate non-canonical TGFp signaling in the fibroblast. We hypothesize that non-canonical TGFp signaling plays a key role in fibrosis during sarcomere-protein based cardiac disease. To'test that, we carry out the experiments described above, but in Tak1- and p38a-loxP targeted mice. Those lines will be crossed to the inducible fibroblast-specific Cre alleles.

Public Health Relevance

Fibrosis often occurs during the development of heart disease. In fact, fibrosis remains a hallmark of hypertrophic cardiomyopathy and is a substrate for arrhythmogenic events, pump dysfunction and, eventually, heart failure. We propose to study how a major cell type in the heart, the fibroblast, contributes to these disease processes. Understanding the roles these cells play will open up novel therapeutic possibilities for impacting favorably on cardiac disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL069779-11
Application #
8460271
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
11
Fiscal Year
2013
Total Cost
$284,482
Indirect Cost
$92,830
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Travers, Joshua G; Kamal, Fadia A; Robbins, Jeffrey et al. (2016) Cardiac Fibrosis: The Fibroblast Awakens. Circ Res 118:1021-40
Schwanekamp, Jennifer A; Lorts, Angela; Vagnozzi, Ronald J et al. (2016) Deletion of Periostin Protects Against Atherosclerosis in Mice by Altering Inflammation and Extracellular Matrix Remodeling. Arterioscler Thromb Vasc Biol 36:60-8
Bernardo, Bianca C; Blaxall, Burns C (2016) From Bench to Bedside: New Approaches to Therapeutic Discovery for Heart Failure. Heart Lung Circ 25:425-34
Valiente-Alandi, Iñigo; Schafer, Allison E; Blaxall, Burns C (2016) Extracellular matrix-mediated cellular communication in the heart. J Mol Cell Cardiol 91:228-37
Xiang, Fu-Li; Guo, Minzhe; Yutzey, Katherine E (2016) Overexpression of Tbx20 in Adult Cardiomyocytes Promotes Proliferation and Improves Cardiac Function After Myocardial Infarction. Circulation 133:1081-92
Fang, Ming; Xiang, Fu-Li; Braitsch, Caitlin M et al. (2016) Epicardium-derived fibroblasts in heart development and disease. J Mol Cell Cardiol 91:23-7
James, Jeanne; Robbins, Jeffrey (2016) Healing a Heart Through Genetic Intervention. Circ Res 118:920-2
Travers, Joshua G; Schafer, Allison E; Blaxall, Burns C (2016) GRK2 in Lymphocytes: Expanding the Arsenal of Heart Failure Prognostics. Circ Res 118:1049-51
Previs, Michael J; Mun, Ji Young; Michalek, Arthur J et al. (2016) Phosphorylation and calcium antagonistically tune myosin-binding protein C's structure and function. Proc Natl Acad Sci U S A 113:3239-44
Gupta, Manish K; McLendon, Patrick M; Gulick, James et al. (2016) UBC9-Mediated Sumoylation Favorably Impacts Cardiac Function in Compromised Hearts. Circ Res 118:1894-905

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